Never offer the devil a ride.He will always want to be in the driving seat…!BK
2CPC 4.2.2George, 62 year old farmer from Tully, presents to his GP with fatigue. His wife has asked him to consult you as his eyes look a bit yellow'. Fatigue: Progressing 2wk. Unable to get out. nausea : no vomiting/haematemesis : no Anorexia, wt loss: yes thinks lost a bit of weight. bowel habit : constipated, stool pale, no blood.
3CPC 4.2.2Fever: no Bleeding/bruising : no cough/dyspnoea : noprevious episodes : 2 x episodes fatigue last 2 years; first attack preceeded by 2 weeks of fever. saw GP - blood tests : 'showed liver not working so well'. then felt better and has not been to see GP since. This time he feels much worse. other PMH of note? 'never sees doc'; has never been in hospital; no regular medication no OTC/herbal remedies SH : married; 3 adult children. Moved to Australia from Greece 26 years ago. Banana farmer
4Laboratory Investigations:FBC: Hb 13.8 g/dl, PCV 45%; WBC 7000/mm3, 70% N, 25% L; Platelets 200,000/mm3 Blood film: Normocytic, normochromic cells Bilirubin: Total serum Bilirubin = 98 μmol/l, (Direct 67)Liver enzymes: Aspartate amino transferase (AST) = 62 U/l Alanine amino transferase (ALT) = 110 U/l Alkaline Phosphatase = 116 U/I Serum Protein: Total protein = 61 g/l, Albumin = 20 g/l, Hepatitis B Surface Antigen (HbsAg): Positive
5Differential Diagnosis:Viral fever -?  Yellow fever, Relapsing fever, Dengue, Ebola, Leptospirosis (common in Tully) - ?Hepatitis – Acute / Chronic - ?Chronic Hepatitis B – why chronic?History & presentation in Hep. A & C ?Other causes of Jaundice?Alcoholic liver disease ?Toxins, chemical, Reyes syndrome?Anemia - ?Malignancy - ?
6Jaundice Clinical Diagnosis
7Pathology of HepatitisViral & AlcoholicDr. Venkatesh M. Shashidhar.Assoc.Prof  & Head of Pathology
81.5 kg, wedge shape4 lobes, Right, left, (Caudate, Quadrate)Double blood supplyHepatic arteriesPortal – Venous bloodNormal
9CT Upper abdomen - NormalLiverStomachAortaSpleenLungLung
Normal Liver - InfantMuch larger, both lobes, below costal margin – palpable*
11Normal Liver
12Normal Liver – MicroscopyAcinus – showing zones 1, 2 & 3.Central VeinBlood FlowPortal Triad
13Structure of Liver LobulePortal Triad: Art, Vein, BD
14Acinus			LobuleFunctional 	 		 Anatomic3Zone 1 – Toxin damage.    		Zone 3 – Ischemic damage
Jaundice15Overproduction of bilirubin
Impaired bilirubin uptake.
Block in metabolism
Impaired transport.
Obstruction to bile excretion.16Liver Function Tests: InterpretationSynthesis / function defect.Total protein & albumin low,  PT prolonged why?Bile Obstruction.Alk Phos – markedly increased – why?Hepatocyte Injury.ALT, AST - high. – why?Alk Phos – moderately increased. – why?Other:GGT – increased with alcohol use. – why?Viral serology - Auto-Antibody panel. Clinical FeaturesFever
Fatigue
Indigestion
Fat intolerance
urine/stool*
Jaundice
Bleeding
Edema
Abd. Distension
Confusion
Coma17Clinical Features - PathogenesisHypoalbuminemia
Hyperammonemia
Hypoglycemia
Palmarerythema
Spider angiomas
Hypogonadism
Gynecomastia
Weight loss
Muscle wasting
Ascites
Splenomegaly
Esophagealvarices
Hemorrhoids
Caput medusae-abdominal skin
Complications of Hepatic Failure
Coagulopathy
Hepatic encephalopathy
Hepatorenal syndromeDecreased Albumin synthesisHepatorenal syndrome
Jaundice in liver failure18
19Diseases of Liver:Hepatitis: Inflammation of LiverViral, Alcohol, immune, Drugs, Toxins, parasitesAcute, Chronic & Fulminant – types.Billiary obstruction – gall stones.Cirrhosis – diffuse scarring & regeneration.Carcinoma - Hepatocellular & Bile duct.Congenital: metabolic, cysts, tumors.
Viral Hepatitis:
21Viral Hepatitis: IntroductionViral Hepatitis:Specific – Heptitis B, C, D (serum),A, ENon-Specific -  Many viruses CMV, EBV, etc.Acute, Chronic (CPH, CAH), Fulminant.Specific viral hepatitis important cause of morbidity & mortality.Horizontal transmission – Blood.. Sex.Vertical transmission – Mother to fetus.Hepatitis  Cirrhosis  Hepatic Ca. (not in A/E)
22Viral Hepatitis: Microbiology
23Hepatitis A'faecal-oral' spread, Travel / exposure. Relatively short incubation period (2-6wk)Epidemics common, may be sporadic. Direct cytopathic virus (immune in B & C)No carrier state – prolonged immunity.Usually mild illness, full recovery usual.Rarely – severe or fulminant.IgM Ab is diagnostic. (no IgG tests).
24Viral Hepatitis A: Serology
25Hepatitis BSpread by blood, Sex & vertical.Relatively long incubation period (4-26wk)liver damage by antiviral immune reaction carrier state exists.Relatively serious infection – chronic, Complications: cirrhosis, carcinoma.Diagnosis: Viral serology (HBsAg)
26Viral Hepatitis B: SerologySequence of serologic markers for hepatitis B viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic infection.
27Pathogenesis of Hepatitis A & B:
28History Hep B Virus:In 1965 - Dr. Blumberg who was studying haemophilia, found an antibody in two patients which reacted against an antigen from an Australian Aborigine. Later the antigen was found in patients with serum type hepatitis and was initially designated "Australia Antigen". Later proved to be hepatitis B virus surface antigen (HBsAg). Dr. Blumberg was awarded the Nobel Prize in 1976.
29Pathogenesis:Ingestion / inoculationReplication - ViremiaLiver – major site replication.Cellular immune response.Apoptosis, necrosis of hepatocytes.Inflammation - Hepatitis Bridging Hepatocyte necrosis (Central vein, portal triad)Fibrosis – patchy/bridgingCirrhosis – extensive fibrosis with loss of archetecture & regenerating nodules.Liver Failure, Coma, Carcinoma..
30Pattern of Liver DamageZonal – Toxin/HypoxiaBridging – Viral & severeInterface – CAH, ImmuneApoptotic – Acute Viral
31Spectrum of Viral Hepatitis:Carrier state / Asymptomatic phaseAcute hepatitis – fever, icterus.Chronic Hepatitis – non specific.Chronic Persistent Hepatitis (CPH)Chronic Active Hepatitis (CAH)Fulminant hepatitis – massive necrosisCirrhosis – total fibrosis.Hepatocellular Carcinoma
32Acute Hepatitis:Swelling and ApoptosisPiecemeal or Bridging, panacinar necrosisDiffuse Inflammation – lymphocytes, Macrophages.Ground glass hepatocytes – HBVMild fatty change – HCV.Portal inflammation and Cholestasis
33Acute viral Hepatitis:
34Acute viral Hepatitis:Apoptotic cells.
35Acute viral Hepatitis:Apoptotic cell.
36Acute viral Hepatitis:
37Acute viral Hepatitis:
38Acute viral Hepatitis C:
39Ground glass Hepatocytes:
40Chronic Hepatitis:Persistent CPHLimited Periportal inflammation. Mild Periportal fibrosisNo hepatocyte Necrosis.LFT normal or mild change.Late cirrhosis Active CAHExtensive Inflammation More fibrosis.Necrosis of hepatocytes.LFT abnormal.Early cirrhosis & other complication.
41Liver Biopsy – viral Hepatitis-C
42Liver Biopsy - CAH:
43Chronic Active viral Hepatitis:
44Chronic Persistent Hepatitis:
45Liver Biopsy – CPH:InflammationNo Necrosis
46Acute - Hepatitis - Chronic
47Viral – Steatosis - AlcoholicMicrovesicular (viral)	Macrovesicular(alcoholic)
48Fulminant Hepatitis:Hepatic failure with in 2-3 weeks.Reactivation of chronic or acute hepatitisMassive necrosis, shrinkage, wrinkledCollapsed reticulin networkOnly portal tracts visibleLittle or massive inflammation – timeMore than a week – regenerative activityComplete recovery – or - cirrhosis.
49Fulminant Hepatitis:
50Fulminant Hepatitis:
51Fulminant Hepatitis:
52Fulminant Hepatitis:confluent necrosis().
53Clinical Spectrum of HBV inf:
54Outcomes of HBV Infection:
“Nearly all men can stand adversity, but if you want to test a man's character, give him power”—  Abraham Lincoln
Laboratory DiagnosisViral Hepatitis
57Viral Hepatitis C: Serology
Hepatitis B – Lab result interpret
59Cirrhosis End stage of diffuse liver disease. scaring with regenerating nodules. (liver failure)Normal        Cirrhosis 
The past has gone and future you cannot see.The present, when you can do something, that is the Gift (Present) with which you can make your future & past memorable.- Sai Baba"The past, the present and the future are really one: they are today."-Harriet Beecher Stowe
Alcoholic Liver Disease
62Incidence is increasing…!
63Chronic Alcoholism:Clinical Features:
64Alcoholic Liver Injury:Ethyl alcohol : Common cause of acute/Chronic liver diseaseAlcoholic Liver disease - PatternsFatty change, Acute hepatitis (Mallory Hyalin)Chronic hepatitis with Portal fibrosis Chronic Liver failureCirrhosisAll reversible except cirrhosis stage.
65Alcoholic Liver Injury: PathogenesisAcetaldehyde – metabolite – hepatotoxicDiversion of metabolism to alcohol Fat  storage – fatty change. Cell swelling..Rupture Fat necrosis  severe inflammation  fibrosis.Alcohol stimulates collagen synthesisInflammation, Portal bridging fibrosisMicronodular cirrhosis.
66Alcoholic Liver DamageIto Cells
67Alcoholic Liver Injury: PathogenesisDiversion of fat metabolism to alcohol – fat  storage.Acetaldehyde – hepatotoxic – denatures ProteinsIncreased peripheral release of fatty acids.Alcohol stimulates collagen synthesisMutant ALDH2 gene with low activity enzyme is observed in Caucasians but is found in some 40% of Orientals (autosomal dominant).Acetaldehyde
68Safe drinking…High RiskIntermediateLow Risk
69Risk of Alcohol injury1 Unit = 10ml = 8gm
70Alcoholic Liver Damage
71Alcohol Toxicity:
72Alcoholic Fatty Liver
73Alcoholic Fatty Liver
74Alcoholic Fatty Liver
75Alcoholic Fatty Liver
Diffuse fatty liver - un-enhanced CT.NormalHamer O W et al. Radiographics 2006;26:1637-1653©2006 by Radiological Society of North America
77Alcoholic Fatty Liver - CT
78Alcoholic Fatty Liver - CT
79Alcoholic Liver- Mallory's hyalin
80Alcoholic Fatty change:
81Alcoholic Fatty change & Mallory Hyalin:
82Alcoholic Fatty Liver
83Alcoholic Fatty Liver - collagen stain
84Alcoholic Cirrhosis:
85Alcoholic Fatty Liver - collagen stain
Alcoholic Hepatitis:86Centrilobular necrosis. Ballooned degenerating hepatocytes (BC) Mallory bodies (MB) Many Neutrophils, few lymphocytes & Macrophages.
The central vein(or terminal hepatic venule (THV), is encased in connective tissue (C) (central sclerosis). Fat-laden hepatocytes (F) are evident in the lobule. The portal tract displays moderate chronic inflammation.87Alcoholic Liver Injury: ComplicationsPancreatitis – Acute or Chronic. Due to ischemic damage to pancreas.Alcoholic hepatitis – similar to viral hepatitis.Fulminant hepatitisAlcoholic Cirrhosis – Micronodular.Alcohol & Medical studentshttp://www.m-c-a.org.uk/about_us/about_mca
Drug Induced Zonal Hepatitis:88Autopsy specimen in a case of acetaminophen overdose.
Prominent hemorrhagic necrosis of the centrilobular zones of all liver lobules.
greater activity of drug-metabolizing enzymes in the central zones.
Other agents that produce such injury are carbon tetrachloride, acetaminophen, toxins of the mushroom Amanita phalloides.
Patients either die in acute hepatic failure or recover without sequelae.Reye Syndrome:89Acute disease of children
Microvesicular steatosis, hepatic failure, and encephalopathy.
Cerebral edema and fat accumulation are reported in the brain.
The symptoms usually begin after a febrile illness, commonly influenza or varicella infection, and are said to correlate with the administration of aspirin,
Pathogenesis remains unknown.
Uncommon, possibly as a result of decreasing use of aspirin in children.Toxemia of Pregnancy:90Hypertension, proteinuria, edema and coagulation abnormalities (pre-eclampsia) and convulsions and coma (eclampsia).
HELLP syndrome (hemolysis, elevated liver enzymes and low platelet count) can also occur in pre-eclamptic women.
Patchy hemorrhages over capsule
Intravascular coagulation
Fibrin thrombi in portal vessels.
Hepatocellular necrosis.91Pathology of Cirrhosis
92Cirrhosis End stage of diffuse liver disease. scaring with regenerating nodules. (liver failure)Normal        Cirrhosis 
93Post hepatitis Liver CirrhosisShrunken, irregular nodularity, (macro nodular) fibrous septa.
94MRI Cirrhosis
95Liver Biopsy – Cirrhosis:
96Liver Biopsy – Cirrhosis
97Liver Biopsy – Cirrhosis
98IntroductionCirrhosis is common end result of many chronic liver disorders.Diffuse scarring of liver – follows hepatocellular necrosis of hepatitis.Inflammtion – healing with fibrosis - Regeneration of remaining hepatocytes form regenerating nodules.Loss of normal architecture & function.
99Etiology of CirrhosisAlcoholic liver disease		60-70%Viral hepatitis			10%Biliary disease			5-10%Primary hemochromatosis	5%Cryptogenic cirrhosis		10-15%Wilson’s, 1AT def		rare
100Alcoholic Cirrhosis
101Micronodular cirrhosis:
102Pathogenesis:Hepatocyte injury leading to necrosis.Alcohol, virus, drugs, toxins, genetic etc..Chronic inflammation - (hepatitis).Bridging fibrosis.Regeneration of remaining hepatocytes Proliferate as round nodules.Loss of vascular arrangement results in regenerating hepatocytes ineffective.
103Clinical FeaturesHepatic encephalopathy
104Pathogenesis of Ascitis:Hepatorenal Syndrome
105Cirrhosis – Portal hypertensionCirrhosis-obstructionPortal hypertensionSplenomegalytransudation - Ascites
106Causes of Portal Hypertension:
107Ascitis in Cirrhosis
108Cirrhosis:
109Ascitis in Cirrhosis
110Gynaecomastia in Cirrhosis????
111Ascitis in congenital Cirrhosis
112Normal / Cirrhosis Liver
113Micronodular cirrhosis:
114Biliary Cirrhosis
115Cirrhosis with bile stasis
116Cirrhosis with bile stasis
117Primary Biliary Cirrhosis - Micronodular
118Liver Biopsy – Cirrhosis
119Palmar erythema & Spider nevi? Pathogenesis
120Hepatocellular Carcinoma
121Cirrhosis with carcinoma:

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Pathology of Hepatitis